HIV-1 AIDS is marked by a significantly higher incidence of tumor development, compared to the general population. Although for some of these malignancies, described as AIDS-defining, the cause is known, the etiology of the AIDS non-defining malignancies remains uncertain. Despite highly active antiretroviral treatments, non-AIDS defining malignancies remain among the leading causes of death in HIV-1 infected individuals. Here we propose to test the hypothesis that HIV-1 infection leads to genomic instability and malignancies because it lifts the natural inhibition on productive replication of endogenous retroviruses. Human endogenous retroviruses (HERVs) occupy a remarkable portion of the human genome. During human evolution the genome has been under constant invasion by retroviruses whose replicative strategy includes integration in the germ-line cells. This phenomenon, known as endogenization, permits the retrovirus to perpetuate itself both vertically and longitudinally. While several host mechanisms have guaranteed the inactivation of most HERVs, there is compelling, albeit circumstantial, evidence implicating endogenous retroviruses in malignancies. HERV production has, indeed, been reported in several types of tumors as well as in HIV-1 infected patients. Cytidine deaminases of the APOBEC3 family (A3) are potent inhibitors of retroviruses. By rendering egressing virions non infectious, A3 molecules potentially prevent HERVs from spreading and inducing oncogenic transformation. We hypothesize that alteration of the existing equilibrium between the seven A3 proteins and HERVs leads to genomic instability due to productive HERV replication. This protective mechanism can be suppressed by different causes, including a) HIV Vif, which efficiently mediates the degradation of several of the A3 molecules, b) genomic structural variation of the A3 locus. Structural genomic variation refers to genomic DNA segments that show copy number variation (CNV) among individuals. The A3 locus has been reported to encompass at least three CNVs, one of which removes the whole APOBEC3B open reading frame. Our experimental strategy will test to what extent suppression of A3 family members (mediated by HIV protein Vif or by A3B genetic deletion polymorphism) de-represses endogenous retroviruses, paving the way to oncogenic transformation via insertional mutagenesis. In our first Specific Aim, we will determine the molecular basis of HIV-1-dependent HERV infectivity. We will test the impact of Vif-mediated release of the A3 restriction on HERV replication in PBMC. In the second Specific Aim we will determine how A3 genomic variation influences HERVs replication. The proposed experiments will establish how (dys)regulation of A3 function affects genome stability in the absence and presence of HIV/AIDS disease. These studies may help develop new markers for malignancies and open doors for the development of new treatment options aimed at stabilizing intrinsic immune defenses.